Full inclusion and exclusion criteria

Inclusion criteria
 Male or female children and adolescents aged 6–17 years old at visit 2
 Written informed consent and assent (where applicable) prior to admission to the trial
 Female subjects of childbearing potential must confirm that sexual abstinence is standard practice and will be continued until 3 months after last drug intake, or agree to use a highly effective method of birth control from 28 days prior to initiation of study treatment, during treatment and until 3 months after last drug intake
 Evidence of fibrosing ILD# on HRCT within 12 months of visit 1 as assessed by the investigator and confirmed by central review
 FVC% predicted ≥25% at visit 2
 Clinically significant disease at visit 2, as assessed by the investigator based on any of the following:
  • Fan score ≥3 [10], or

  • Documented evidence of clinical progression over time based on either:

    •   o 5–10% relative decline in FVC% predicted accompanied by worsening symptoms, or

    •   o a ≥10% relative decline in FVC% predicted, or

    •   o increased fibrosis on HRCT, or

    •   o other measures of clinical worsening attributed to progressive lung disease (e.g. increased oxygen requirement, decreased diffusion  capacity)

Exclusion criteria
 AST and/or ALT >1.5×ULN at visit 1+
 Bilirubin >1.5×ULN at visit 1+
 Creatinine clearance <30 mL·min−1 calculated by Schwartz formula at visit 1+
 Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment) at visit 1
 Previous treatment with nintedanib
 Other investigational therapy received within 1 month or 5 half-lives (whichever is shorter but ≥1 week) prior to visit 2
 Significant PAH defined by any of the following:
  • Previous clinical or echocardiographic evidence of significant right heart failure

  • History of right heart catheterisation showing a cardiac index ≤2 L·min−1·m−2

  • PAH requiring parenteral therapy with epoprostenol/treprostinil

 Other clinically significant pulmonary abnormalities (investigator-assessed)
 Cardiovascular diseases (any of the following):
  • Severe hypertension (uncontrolled with treatment), within 6 months of visit 1; uncontrolled hypertension is defined as:

    •   o Children aged 6–≤12 years: ≥95th percentile+12 mmHg or ≥140/90 mmHg (whichever is lower) (systolic or diastolic blood pressure equal to or greater than the calculated target value)

    •   o In adolescents aged 13–17 years: systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg

  • Myocardial infarction within 6 months of visit 1

  • Unstable cardiac angina within 6 months of visit 1

 Bleeding risk, defined as any of the following:
  • Known genetic predisposition to bleeding

  • Patients who require:

    •   o Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors, heparin, hirudin)

    •   o High-dose antiplatelet therapy§

  • History of haemorrhagic CNS event within 12 months of visit 1

  • Any of the following within 3 months of visit 1:

    •   o Haemoptysis or haematuria

    •   o Active gastrointestinal bleeding or gastrointestinal ulcers

    •   o Major injury or surgery (investigator-assessed)

  • Any of the following coagulation parameters at visit 1:

    •   o INR >2

    •   o Prolongation of PT by >1.5×ULN

    •   o Prolongation of aPTT by >1.5×ULN

 History of thrombotic event (including stroke and transient ischaemic attack) within 12 months of visit 1
 Known hypersensitivity to the trial medication or its components (i.e. soya lecithin)
 Documented allergy to peanut or soya
 Other disease that may interfere with testing procedures or in the judgement of the investigator may interfere with trial participation or may put the patient at risk when participating in this trial
 Life expectancy for any concomitant disease other than ILD <2.5 years (investigator-assessed)
 Female patients who are pregnant, nursing, or who plan to become pregnant while in the trial
 Patients not able or willing to adhere to trial procedures, including intake of study medication
 Patients with any diagnosed growth disorder such as growth hormone deficiency or any genetic disorder that is associated with short stature (e.g. Turner syndrome, Noonan syndrome, Russell–Silver syndrome) and/or treatment with growth hormone therapy within 6 months before visit 2ƒ
 Patients <13.5 kg of weight at visit 1 (same threshold for male and female patients)

ALT: alanine aminotransferase; aPTT: activated partial thromboplastin time; AST: aspartate aminotransferase; CNS: central nervous system; FVC: forced vital capacity; HRCT: high-resolution computed tomography; ILD: interstitial lung disease; INR: international normalised ratio; PAH: pulmonary arterial hypertension; PT: prothrombin time; ULN: upper limit of normal. #: Clinically significant fibrosing ILD will be confirmed based on documented evidence of fibrosing features on HRCT or lung biopsy, as defined in the Participants section of the Methods. : predicted normal values will be calculated according to the Global Lung Initiative. +: laboratory parameters from visit 2 will only be available after randomisation and, if the result no longer satisfies the entry criteria, the investigator will decide whether the patient should remain on study drug. Abnormal laboratory parameters at visit 1 are allowed to be re-tested (once) if it is thought that there was a measurement error or if they are a result of a temporary and reversible medical condition (once that condition has resolved). §: prophylactic low-dose heparin or heparin flush as needed for maintenance of an indwelling intravenous device, as well as prophylactic use of antiplatelet therapy, are not prohibited. ƒ: patients with short stature considered by the investigator to be due to glucocorticoid therapy may be included.